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Abstract

Background Changes in the cerebral hemispheric white matter are detected with increasing frequency by CT and MRI among persons older than 60 years. The pathogenesis, clinical significance, and morphological substrate of these changes are incompletely understood. Patients who have such neuroimaging abnormalities are sometimes diagnosed with “Binswanger’s disease,” an eponym that has generated much confusion because of its imprecise meaning. The objectives of this study were to determine whether the term Binswanger’s disease merits acceptance as a distinct clinicopathologic entity, to deduce the clinical significance of these white matter abnormalities from the analysis of appropriate publications, and to evaluate studies that correlate in vivo changes in the cerebral white matter with pathological features.

Summary of Review We evaluated Binswanger’s original case description and, after conducting a Medline search, reviewed more than 160 publications, mostly in the English language, on the subject of white matter abnormalities detectable by currently used neuroimaging methods (ie, leukoaraiosis).

Conclusions Binswanger’s original description appears to be insufficient for the purpose of defining a new nosological entity. After evaluating the vaguely outlined pathological correlates described in a few of these subcortical cerebral leukoencephalopathies, we conclude that the clinical significance of leukoaraiosis remains incompletely defined. However, its frequency increases with age independent of other risk factors, and in nondemented subjects leukoaraiosis is associated with deficits in selected cognitive functions. Moreover, leukoaraiosis correlates with an increased risk for the subsequent development of strokes. We make specific suggestions for future studies that may help to clarify this topic.

The application of CT in the 1970s and the subsequent application of MRI to image the intracranial contents have revealed an unexpected number of changes in the cerebral white matter of both asymptomatic and cognitively impaired individuals.

The pathogenesis, clinical significance, and pathological substrate of these white matter alterations are incompletely understood. Even the optimal term to designate these changes is controversial; some authors assume that the cerebral white matter changes (demonstrated by CT or MRI) are synonymous with “Binswanger’s disease” (an eponym of nebulous meaning), while others use the term leukoaraiosis to refer to all white matter changes visible on neuroimaging studies.

We reviewed a selected number of publications, most of which appeared after 1979, for the purpose of (1) determining whether the term Binswanger’s disease merits its acceptance as a distinct clinicopathologic entity, (2) summarizing a large and controversial number of publications dealing with the clinical relevance of white matter abnormalities detected by either CT or MRI, and (3) evaluating studies based on the correlation observed between in vivo observations and histopathological analysis of cerebral white matter.

Historical Overview

In 1894, in a lengthy manuscript dealing with the differential diagnosis of general paresis of the insane, Otto Binswanger described the case of a syphilitic man in his mid-fifties who had developed a progressive decline in mental functions characterized by speech and memory disorders, depression, and personality changes, accompanied by diminished motor power in the lower extremities and slight hand tremor.12 At autopsy, the dura mater at the base of the skull showed granular deposits; there was also minimal intracranial atherosclerosis, considerable enlargement of the lateral ventricles, marked atrophy of the cerebral white matter, and multiple ependymal thickenings.12

Binswanger neither provided microscopic descriptions nor illustrated any findings of this single case; an additional seven cases were mentioned in a footnote, but these cases were never further described. In subsequent publications Binswanger did not deal again with the topic of white matter disease, and in fact he did not attribute much significance to the case included in his 1894 report.3 In 1902 Alzheimer,45 referring to the case described by his mentor Otto Binswanger, added a short histological description of what he considered was an analogous case and intuitively attributed the white matter changes to arteriosclerosis of the long penetrating vessels. In 1962 J. Olszewski,6 after careful review of Binswanger’s original report, suggested that the lesions in the dura mater and in the ependyma, together with the history of syphilis, made Binswanger’s a likely case of neurosyphilis; accordingly, he proposed the term subcortical arteriosclerotic encephalopathy to describe “a form of cerebral arteriosclerosis in which vessels of the white matter and subcortical grey matter are affected predominantly.”6 Significantly, as of 1987 when Babikian and Ropper7 wrote a review, the pathological diagnosis of this obscure entity (Binswanger’s disease or subcortical arteriosclerotic encephalopathy) was limited to fewer than 50 cases.

Contemporaneously, the diagnosis of Binswanger’s disease (ie, cerebral white matter abnormalities) had acquired new popularity after the introduction of CT and its first diagnosis based on clinical and CT findings.8 The increasing availability of CT and MRI led many to assume that Binswanger’s disease could be diagnosed premortem.9101112131415 However, it soon became apparent that alterations of the hemispheric white matter (detected by either CT or MRI) were common in both symptomatic and asymptomatic subjects. Román1617 suggested that among asymptomatic individuals, the white matter abnormalities seen on CT or MRI might represent an early form of Binswanger’s disease.

Today it seems impossible to determine with certainty the nature of the disease affecting the patient vaguely described by Binswanger, but it seems reasonable to conclude that Binswanger’s description cannot be applied to what was later considered a form of dementia secondary to cerebral atherosclerosis.16 Moreover, it may be futile to label patients showing radiological white matter abnormalities of unknown origin as having a disease for which definite clinical or pathological criteria do not exist. For these reasons we suggest that the eponym Binswanger’s disease lacks medical significance or relevance.

Leukoaraiosis

Definition

In an attempt to overcome the tendency to identify a neuroimaging abnormality with a vaguely defined disease process, Hachinski et al1819 introduced the term leukoaraiosis (from the Greek leuko [white] and araiosis [rarefaction]) to designate periventricular or subcortical (centrum semiovale) areas of hypodensity on CT or hyperintensity on T2-weighted MRI whose origin deserves further elucidation. The term leukoaraiosis (LA) refers to both the CT- and MRI-detectable alterations, although the lesions are not completely superimposable as to number, site, and extension.2021222324252627 Also, some authors suggest that MRI can detect LA at an earlier stage than CT.28 For these reasons, in this review we discuss LA as seen separately on CT and MRI.

Frequency

LA is frequently detected by CT and MRI both in asymptomatic persons older than 60 years and in cognitively impaired individuals, especially those who have evidence of either cerebrovascular disease or risk factors associated with stroke.29 Among patients with dementia of presumed vascular origin (VaD), LA is detected by CT in 41% to 100%2030313233343536373839 and by MRI in 64% to 100% of the cases.20304041424344454647 This increased frequency of LA among patients who have risk factors associated with vascular disease is one of the clues suggesting a possible ischemic pathogenesis for LA. Thus, it is intriguing that a large proportion of Alzheimer’s disease (AD) patients (ranging from 19% to 78% in CT-based studies2030313233343538394849505152535455 and from 7.5% to 100% in MRI studies202230404243444547525657585960 ) have LA, although usually the changes in white matter density are less severe in AD patients than in those with cerebrovascular disorders.404244474861 White matter abnormalities in patients with AD, according to some authors, might be associated with cerebral congophilic angiopathy, one of the microscopic hallmarks of AD.6263

LA in normal control subjects is usually less severe than in demented patients,455764 yet LA is detected in up to 21% of asymptomatic subjects evaluated with CT3031323949505265 and in up to 100% among those evaluated with MRI.2227304042434445525657606166676869707172737475 Inference on the prevalence of LA in the normal population cannot be deduced from these investigations because the definition of normal subjects varies in each study. Two recent population-based studies7677 reported MRI-detectable LA (MRI-LA) in 27% and 38% of subjects with a mean age greater than 65.

A wide discrepancy exists among reports dealing with the frequency of LA. This can be attributed to the inclusion of subjects with different ages, variably associated cerebrovascular risk factors and, in MRI studies, application of diverse strengths of magnetic field and variations in pulse sequence, as well as on different definitions of MRI-LA. A frequently used classification separates MRI-LA into periventricular and deep subcortical lesions and grades each according to its severity.40 Periventricular MRI-LA is detected more frequently than deep subcortical (centrum semiovale) MRI-LA; however, not all authors considered these lesions separately.222561787980

Effect of Aging and Cerebrovascular Risk Factors

Both the frequency and the severity of CT-detectable LA (CT-LA) and MRI-LA increase with aging, as reported in patients with diverse diseases,15253044567278798081828384858687888990 in normal volunteers,2249566168697071737475768283909192939495 and in two population-based studies.7793 Only a minority of studies found a lack of correlation between aging and either the presence or severity of MRI-LA.41447196 With the exception of one CT-based study,32 the association between LA and aging exists independent of the increased presence of vascular risk factors in persons older than 60 years (Table⇓).477682848795979899

Arterial hypertension is commonly associated with changes in the white matter detectable by CT. This association exists in patients with cerebrovascular accidents and dementia35505481100101 as well as in asymptomatic control subjects.49 The exclusion of patients with chronic hypertension from the diagnosis of AD may explain why in some studies there was no increased frequency of hypertension among AD patients with CT-LA.495181 However, when the importance of history of stroke and of hypertension are contemporaneously evaluated, the former becomes equal97 to or more important3299 than hypertension as a predictor of LA (Table⇑). Evidence of CT-LA, in particular, correlates with lacunar infarcts97 and intracerebral hemorrhage,102 two entities that have a close association with arterial hypertension. It seems surprising that one study reported an association between CT-LA and a systolic blood pressure lower than 130 mm Hg, together with evidence of heart failure.39 Probably this is because hypertension plays a fundamental role in the development of early changes affecting the long penetrating arteries of the white matter.103 After arteriolosclerotic changes such as hyalinization begin to affect many cerebral blood vessels, transient decreases in cerebral blood flow (as elicited by cardiac dysrhythmia, improper administration of antihypertensive therapy, or failure of autoregulatory mechanisms, as recently demonstrated in patients with CT-LA104 ) could lead to ischemic injury of the periventricular white matter. The periventricular white matter corresponds to a terminal field, and this could make it selectively vulnerable to changes in blood pressure.105 The fact that the degree of carotid stenosis does not influence the severity of LA99 indirectly supports the view that LA is closely linked to disease of small arteries and arterioles.

An association between LA and risk factors for cerebrovascular disease has been shown repeatedly by MRI-based studies.1526274456667074757879808588106107 The application of multivariate analysis does not provide concordant results among all the studies reviewed (Table⇑); nevertheless, it appears reasonable that risk factors associated with cerebrovascular disease may worsen a process such as LA, which is sensitively influenced by aging.

Cognitive Impairment

Few topics in neurology are as controversial as the issue of whether LA may influence the severity of cognitive impairment among demented patients or the cognitive prowess of otherwise normal subjects.

A correlation between cognitive impairment and the presence or severity of CT or MRI-LA has been inconsistently reported in AD patients4043455355565996108 and in studies that failed to specify the type of demented patients included.2130426188 Among patients with dementia of presumed vascular origin, only the severity of LA (graded on MR images46106109 ) rather than its presence (on CT32110 ) correlates with the degree of dementia.

Although seeking cognitive abnormalities in normal subjects with LA might appear tautological, a few studies have shown that CT-LA111 or MRI-LA43676869107 does not significantly influence the general cognitive profile of normal volunteers.

Because aging as well as other associated factors may influence cognitive performances, the use of multivariate analyses is essential in this evaluation. After controlling for the possible confounding effects of age, sex, level of education, and the neuroimaging evidence of brain infarcts, CT-LA correlates with low neuropsychological scores in nondemented subjects.65 Among cognitively impaired patients, CT-LA is not associated with the diagnosis of dementia32 ; however, these patients show a trend toward low cognitive performance with respect to demented patients without CT-LA.48 In contrast, multivariate analysis results based on MRI data partially deny that LA would affect cognition in nondemented patients84 or in normal subjects.697475 One possible explanation for the disparity in the results obtained by CT- and MRI-based studies is that MRI tends to detect a larger number of milder lesions than CT, and it is therefore less specific. In fact, a significant difference in cognitive and neurobehavioral functions is found when normal volunteers with a marked degree of MRI-LA are compared with those without LA.9394 Quantitating the severity of MRI-LA may be necessary in future studies. A threshold exists between the extent of MRI-LA and subtle cognitive impairment; among 100 volunteers participating in a single study, those in whom MRI-LA involved an area greater than 10 cm2 had significant decreases in cognitive performances involving frontal lobe abilities, attention, and speed of information processing.73 An added possible cause of inconsistency among various studies may derive from the application of neuropsychological tests that are acceptable for screening purposes but are inadequate to detect subtle or specific cognitive functional changes; for example, among patients with the same severity of dementia, tests that evaluate individual cognitive areas revealed differences depending on the presence or absence of periventricular MRI-LA.4244 Among nondemented subjects, MRI-LA influences mental tasks involving speed of mental processing and attention.28759095107 Because not all of these differences are obvious, their clinical significance should be reexamined. Two studies report that subjective memory impairment is more frequently noted by subjects with MRI-LA than by those without LA.2877

In evaluating the effect of neuroimaging abnormalities on cognitive prowess, atrophy of corpus callosum and enlarged caliber of the lateral ventricles should be weighed; both of these could be equally as important93109112 as or more important113 than LA in determining cognitive deterioration. The marked atrophy of the cerebral white matter in advanced stages of leukoencephalopathy may lead to ex vacuo enlargement of the lateral ventricles; at least one study has shown a positive correlation between the severity of MRI-LA and ventricular enlargement.93

Other Clinical Findings

In addition to cognitive impairment, gait disturbances,3149656897 tendency to fall,111 extensor plantar reflex,486597 and primitive reflexes659097 are the most common neurological abnormalities associated with LA, and their existence is thought to be related to injury to the subcortical brain regions. An increased prevalence of MRI-LA has been recently described in a variety of psychiatric disorders.80114115116117118119120121122123124125 However, some of these studies are noncontrolled, are based on small numbers of patients, and do not take into account associated risk factors; therefore, many of these observations await corroboration.

Prognostic Significance

The presence of LA in patients with history of cerebrovascular accidents101126 or probable AD55 suggests an increased incidence of subsequent stroke. However, LA may be only one of the poor prognosis indicators; the true determinants are aging, arterial hypertension, presence of lacunes on CT, and electrocardiographic abnormalities.127 LA does not seem to influence the progression of global cognitive impairment in AD patients,86108128 and in normal subjects LA is associated only with a more rapid decline in visuospatial, associative, and psychomotor functions.92 A clinicopathologic study showed early death occurrence and faster progression of mental impairment among AD patients who had pathological evidence of more severe decrease in the number of myelinated fibers, suggesting that the severity of LA, rather than its presence, is a reliable prognostic factor.62

CADASIL

Recently a condition first described in 1977129 and characterized by multiple subcortical infarcts, leukoencephalopathy, and an autosomal dominant pattern of inheritance (CADASIL [cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy]) has received new attention after the genetic defect was mapped to chromosome 19q12.130 CADASIL is clinically characterized by recurrent strokes and a terminal picture of dementia; pathologically, small deep infarcts and leukoencephalopathy are associated with a concentric thickening of the wall of the small vessels secondary to granular eosinophilic deposits in the tunica media.131132 At present, CADASIL accounts for only a very small number of cases with LA,133 but close study of this condition could shed light on the pathogenesis of white matter abnormalities related to small-vessel disease.

Pathological Correlates

Understanding the pathological correlates of LA might help to elucidate the pathogenesis of these lesions. The correlation between LA and postmortem findings has been evaluated in cases in which CT or MRI showed LA at a time closely related to autopsy or in cases in which postmortem MRI examination of the brain was completed. Although fewer white matter abnormalities are noted postmortem compared with in vivo MRI,134 the postmortem observations are considered valuable.135136

Periventricular LA correlates with decreased myelin content,137138139140141142143144 loss of ependymal cell layer and reactive gliosis (also called granular ependymitis) at the tip of the frontal horns,137138139140141143145 increased periependymal extracellular fluid content, and smaller and fewer axons.138 Some authors have also found enlarged perivascular spaces at this periventricular location.141 Small periventricular lesions exist in all age groups (including newborns)138144 ; therefore, such findings probably do not constitute a true abnormality.

The histological correlates of deep subcortical MRI-LA are even less consistent than those noted for periventricular LA. Punctate abnormalities correspond to enlarged perivascular spaces,137143 small cavitary infarcts (or lacunes),146147148 demyelinating plaques, brain cysts, and congenital diverticula of the lateral ventricles.147 MRI methods seem adequate to distinguish between enlarged Virchow-Robin spaces and lacunar infarcts,145149 but in some cases the corresponding pathological abnormality of punctate lesions was undetectable.134142147148 The more diffuse lesions in the centrum semiovale have been related to myelin rarefaction that spares the U fibers,135137 sometimes accompanied by astrogliosis,139 and to diffuse vacuolization of the white matter.148 The myelin rarefaction does not correspond to true demyelination since the process also involves destruction of the axons.62135150151 Thickening of the wall of the small vessels is also found in these areas.135139140142146151 For these diffuse subcortical lesions the radiological-pathological correlation is not very tight: myelin loss is sometimes present in areas without LA151 or is more extensive than shown by MRI.151

Conclusions

Nomenclature

According to some authors Binswanger’s disease has well-defined neuropathological features,152153154 while others suggest validation of clinical criteria155 based on pathological characteristics attributed to Olszewski.6 However, the pathological criteria remain vaguely outlined, and Binswanger’s original description is clearly insufficient to define a new nosological entity. Many cases described under the eponym Binswanger’s disease share some pathological findings,716156157 but the same type of histological abnormalities can also be seen in a wide variety of unrelated conditions.63158159 We believe that the term Binswanger’s disease should be avoided. Instead, the more descriptive terms of LA and subcortical leukoencephalopathy can be reserved for the radiological and pathological communications.

Clinical Significance of LA

The clinical significance of LA remains incompletely defined. However, some conclusions seem warranted at this time. (1) LA is part of the aging process; the addition of cerebrovascular risk factors aggravates LA. (2) In subjects who have no or only moderate cognitive impairment, LA, especially of the most severe degrees, influences specific cognitive functions, such as those involving speed of mental processes. LA may also contribute to the cognitive decline in patients with AD and VaD, but to demonstrate a correlation once the dementia is fully developed is extremely arduous. (3) Persons with LA have an increased risk of cerebrovascular events. It remains to be shown whether this conclusion can be applied only to specific categories of patients, eg, those with previous cerebrovascular accidents.

Possible Causes of Inconsistency in Past Studies

Uncertainties regarding the significance of LA stem from our poor understanding of its pathogenesis160161 and the incomplete definition of its pathological features. Factors that may account for the discrepancy in results obtained in large numbers of epidemiological studies include (1) small numbers and heterogeneous cohorts of patients, (2) application of different classifications of LA, and (3) use of disparate neuropsychological tests. An added source of possible variability includes poor interobserver agreement on the radiological assessment of LA; among CT-based studies this agreement was substantial in three96102162 and almost perfect in two studies.99163 The interobserver agreement in the evaluation of MRI-LA was moderate in one,96 substantial in three,5687164 and almost perfect in another study.76

Future Approaches

Three future endeavors are recommended: (1) to define the responses of white matter to various types of ischemic injury in suitable experimental models, (2) to explore the potential vascular pathogenesis of specific types of leukoencephalopathy associated with a genetic pattern of inheritance, and (3) to investigate the clinical and pathological correlates of distinct degrees of severity of LA (especially MRI-LA) in well-defined populations and at specific brain locations. In this context the adoption of a uniform neuroimaging nomenclature and the application of uniform and specific neuropsychological tests will be invaluable. A multicenter study could provide the large number of observations necessary to conduct the required statistical analyses.